Bortezomib, Melphalan, and Dexamethasone in Treating Patients With Primary Amyloidosis or Light Chain Deposition Disease

A Multicenter Phase II Trial of Bortezomib (Velcade), Melphalan, and Dexamethasone (V-MD) in Patients With Symptomatic AL-Amyloidosis or Light Chain Deposition Disease

RATIONALE: Giving bortezomib together with melphalan and dexamethasone may be an effective treatment for primary amyloidosis and light chain deposition disease.

PURPOSE: This phase II trial is studying how well giving bortezomib together with melphalan and dexamethasone works in treating patients with primary amyloidosis or light chain deposition disease.

Study Overview

• Status: Completed
• Conditions: Primary Systemic Amyloidosis; Light Chain Deposition Disease
• Intervention / Treatment: Drug: bortezomib; Drug: dexamethasone; Drug: melphalan; Genetic: microarray analysis; Other: flow cytometry; Other: laboratory biomarker analysis; Procedure: quality-of-life assessment

Detailed Description

OBJECTIVES:

Primary

• Determine the complete hematologic response rate at 12 months.

Secondary

• Determine the overall hematologic response rate.
• Determine the organ response rate.
• Determine time to treatment failure.
• Determine the overall survival.

OUTLINE: This is a multicenter study.

Patients receive oral melphalan on days 1-4, bortezomib IV on days 1, 8, 15, and 22, and dexamethasone orally or IV on days 1, 2, 8, 9, 15, 16, 22, and 23. Treatment repeats every 4-6 weeks for up to 20 courses in the absence of disease progression or unacceptable toxicity.

Blood, urine, and bone marrow aspirates are collected at baseline and periodically after treatment to permit the correlation of clinical results with measured molecular events. A single baseline peripheral blood DNA sample is collected for future association studies linking disease onset, progression, and response to administered therapy with single nucleotide polymorphisms. Blood plasma and urine samples are evaluated for proteomic markers associated with disease progression and therapeutic response. Peripheral blood RNA samples are evaluated for transcriptional response to treatment of peripheral blood lymphocytes. Bone marrow aspirates are collected to extract plasma cells by flow cytometry for gene expression profiling.

Quality of life is assessed at the beginning of each course.

• Study Type: Interventional
• Enrollment (Actual): 35
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Colorado
    • Denver, Colorado, United States, 80218
      • Rocky Mountain Cancer Centers/Rocky Mountain Blood & Marrow Transplant Program
  • Massachusetts
    • Boston, Massachusetts, United States, 02118
      • Boston University Cancer Research Center
  • Michigan
    • Detroit, Michigan, United States, 48202
      • Josephine Ford Cancer Center at Henry Ford Hospital
    • Detroit, Michigan, United States, 48201-1379
      • Barbara Ann Karmanos Cancer Institute
    • Southfield, Michigan, United States, 48075
      • Providence Cancer Institute at Providence Hospital - Southfield Campus
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke Comprehensive Cancer Center
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15232
      • UPMC Cancer Centers

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 120 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

DISEASE CHARACTERISTICS:

• Biopsy-proven diagnosis of 1 of the following:

  • Primary systemic amyloidosis

    • Histochemical diagnosis of amyloidosis determined by polarizing microscopy of green bi-refringent material in Congo red-stained tissue specimens or characteristic electron microscopy appearance
  • Light chain deposition disease

• Measurable disease as defined by one or more of the following:

  • Serum monoclonal protein ≥ 0.5 g/dL by serum electrophoresis
  • Urine monoclonal protein > 200 mg/tv in a 24 hr urine electrophoresis
  • Serum immunoglobulin free-light chain ≥ 10 mg/dL AND abnormal serum immunoglobulin kappa lambda free light chain ratio

• Must meet 1 of the following criteria:

  • Clonal population of plasma cells in the bone marrow (≤ 30%)
  • Immunohistochemical stain with anti-light chain anti-sera of amyloid fibrils

• Must not meet the following diagnostic criteria for symptomatic* multiple myeloma:

  • Lytic lesions on skeletal survey
  • Plasmacytoma
  • Increase in bone marrow plasma cells ≥ 30% NOTE: *Patients who meet the International Myeloma Working Group definition of symptomatic multiple myeloma with symptoms attributable only to associated amyloidosis and who do not otherwise meet the criteria for diagnosis of smoldering myeloma are potentially eligible upon approval of the principal investigator.

• If not previously treated, patient is either not a candidate for autologous stem cell transplantation (ASCT) or has declined the option of ASCT

  • Patients who have undergone prior ASCT and have subsequently progressed are eligible, provided other eligibility criteria are met
• No secondary or familial amyloidosis

PATIENT CHARACTERISTICS:

• ECOG performance status 0-3
• Creatinine < 5 mg/dL
• Bilirubin < 2.5 times upper limit of normal (ULN)
• ALT and AST < 3 times ULN
• Absolute neutrophil count ≥ 1,000/mm³
• Platelet count ≥ 80,000/mm³
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• Peripheral sensory neuropathy < grade 3
• No myocardial infarction within the past 6 months
• No New York Heart Association class III or IV heart failure
• No uncontrolled angina
• No severe uncontrolled ventricular arrhythmias
• No EKG* evidence of acute ischemia or active conduction system abnormalities (not including 1st degree AV-block, Wenckebach type 2nd degree heart block, or left bundle branch block) NOTE: *Prior to study entry, any EKG screening abnormality must be documented by the investigator as not medically relevant; there is no lower limit of LVEF below which patients are excluded from participation
• No hypersensitivity to bortezomib, boron, or any of the other agents utilized in this study
• No serious concurrent illness (e.g., stroke) within the past 30 days
• No psychiatric illness likely to interfere with study participation

• No untreated HIV infection

  • Patients with asymptomatic HIV infection on active antiretroviral therapy are potentially eligible
• No diagnosis or treatment of another malignancy within the past 3 years, except completely resected basal cell or squamous cell carcinoma of the skin, an in situ malignancy, or low-risk prostate cancer after curative therapy

PRIOR CONCURRENT THERAPY:

• See Disease Characteristics
• No other investigational drugs within the past 14 days

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Melphalan, Dexamethasone, Bortezomib,; Bortezomib 1.3 mg/m2 days 1, 8, 15, 22; Dexamethasone 40 mg/d days 1, 2, 8, 9, 15, 16, 22, 23; Melphalan 9 mg/m2/day days 1-4

Drug: bortezomib; Bortezomib 1.3 mg/m2 days 1, 8, 15, 22; Other Names: Velcade; Drug: dexamethasone; Dexamethasone 40 mg/d days 1, 2, 8, 9, 15, 16, 22, 23; Other Names: Decadron; Hexadrol; Dexasone; Dexamethasone Acetate; Maxidex; Dexamethasone Sodium Phosphate; Diodex; Drug: melphalan; Melphalan 9 mg/m2/day days 1-4; Other Names: L-PAM; L-Sarcolysin; Phenylalanine Mustard; Alkeran®; Genetic: microarray analysis; ≤28 days prior to enrollment; Other: flow cytometry; Day 1 of cycles 6, 12, 18 and at end of study.; Other: laboratory biomarker analysis; ≤28 days prior to enrollment; Procedure: quality-of-life assessment; Start of each cycle

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Complete Hematologic Response	Up to 12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Organ Response Rate (OrR)		Beginning of cycles 4, 8, 12, 16 and 20, at follow up and end of study.
Overall Hematologic Response Rate (OHR)		Beginning of cycles 4, 8, 12, 16 and 20, at follow up and end of study.
Overall Survival	time from day of registration until day of death.	time from day of registration until 72 months.
Time to Treatment Failure (TTF)	Time from start of treatment until date of documented disease progression, removal from protocol due to toxicity, or death from any cause.	start of treatment until 72 months

Collaborators and Investigators

• Sponsor: Barbara Ann Karmanos Cancer Institute
• Collaborators: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Jeffrey A. Zonder, MD, Barbara Ann Karmanos Cancer Institute

Publications and helpful links

Helpful Links

• Clinical trial summary from the National Cancer Institute's PDQ® database

Study record dates

Study Major Dates

• Study Start: September 1, 2007
• Primary Completion (Actual): October 1, 2010
• Study Completion (Actual): June 6, 2019

Study Registration Dates

• First Submitted: August 24, 2007
• First Submitted That Met QC Criteria: August 24, 2007
• First Posted (Estimated): August 27, 2007

Study Record Updates

• Last Update Posted (Actual): December 22, 2023
• Last Update Submitted That Met QC Criteria: December 20, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: primary systemic amyloidosis; light chain deposition disease
• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Metabolic Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Proteostasis Deficiencies; Neoplasms, Plasma Cell; Multiple Myeloma; Immunoglobulin Light-chain Amyloidosis; Amyloidosis; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protease Inhibitors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Dexamethasone; Dexamethasone acetate; BB 1101; Melphalan; Bortezomib; Dexamethasone 21-phosphate
• Other Study ID Numbers: 2006-132; P30CA022453 (U.S. NIH Grant/Contract); MILLENNIUM-WSU-2006-132 (Barbara Ann Karmanos Cancer Institute); WSU-HIC-060907M1F (Other Identifier: Wayne State University - Human Investigation Committee)